This proposal describes theoretical approaches for relating structural features of ion channel proteins and of their phospholipid environment to channel behavior and function, stressing problems central to excitable cell physiology and controlled water transport. The calculations are designed to clarify issues in permeation and gating. A new approach to determining reaction pathways in proteins, ones involving large energy barriers, is outlined. It is based on available crystallographic data and used to determine permeation pathways in systems, like CIC chloride channels, where the paths cannot be established by structural inspection. It is used to identify the cooperative, low frequency, high amplitude vibrational modes that control gating. It is applied to CIC chloride channels to establish the mechanism that couples conductance with the fast gate and to search for the structural factors that control the slow gate. It is applied to aquaporins to better characterize the mechanism of proton rejection, and to elucidate the physical basis for high water turnover and for water/alditol selectivity. It is applied to potassium channels to clarify how coupling between the cations and the selectivity filter leads to C-type inactivation and influences normal activation, to reconcile contradictions between structural and electrophysiological studies of the voltage sensor and to elucidate the mechanism of voltage gating. Channel-membrane interaction influences gating, most clearly for mechanically gated assemblies. A new, efficient way to treat membrane-mediated influences between a channel's transmembrane segments is outlined. It will be validated on alamethecin and used to better characterize gating of the MscL channel.